Interleukin-1 and Steroid Signaling Drive Toxoplasma-induced Prostatic Hyperplasia

摘要 炎症在成人前列腺中非常常见，它与良性前列腺的发展有关。 前列腺增生症(BPH)。我们不知道前列腺癌发炎的主要原因是什么，我们也不知道 了解它是如何促进男性前列腺癌的，但提出的机制包括释放分子 来自促进前列腺生长的炎症细胞，以及体内类固醇激素水平的增加 前列腺癌是对炎症的反应。缺乏一个完整的模型系统来模拟人类的各个方面 良性前列腺增生症是造成这一知识鸿沟的关键原因。在晚期和高度非小细胞肺癌的病理特征中 症状性前列腺增生症是上皮内增生的特征性增生性环状结构，称为 “微腺体增生症”。这一术语源于小微腺体的组织结构。 在上皮性结节内形成。与其他炎症诱导的啮齿动物增殖模型不同 前列腺癌，我们最近发表的弓形虫前列腺炎模型导致了这种组织学上的改变 在人类中观察到的模式，并与类似于人类BPH的症状有关，包括 尿频增加，尿量减少。这表明，诱导两者的机制 细胞增殖和组织构型可能会将炎症与增生和前列腺疾病联系起来，而我们的 引入这两种成分的弓形虫模型将允许我们测试这一想法。我们的假设是T. 贡地诱导的慢性前列腺炎通过促进细胞因子介导的生长促进前列腺增生 雌激素和睾酮的因子信号和从头生物合成。人类前列腺增生症 与IL-1和IGF-1活性增加有关。因此，在我们的第一个目标中，我们建议确定 弓形虫感染诱导的慢性炎症通过激活IL-1诱导前列腺增殖 IGF-1途径。为此，我们将使用分子和药理学方法相结合的方法来评估 炎症诱导的IL-1和IGF-1在体内的表达和产生与增生性疾病和 弓形虫感染的前列腺癌患者的尿路症状。在第二个目标中，我们将确定弓形虫诱导的 微腺体增生症是由诱导前列腺合成新的类固醇激素引起的，我们将 评估可药物靶标CYP17A1以及雄激素和雌激素受体在这一过程中的作用。我们 还将研究弓形虫如何诱导类固醇合成的机制。最后，我们将确定是否 CYP17A1驱动的类固醇合成与人类炎症和微腺体增生相关 前列腺增生症。已知雄激素和雌激素的从头合成发生在BPH患者的前列腺中。我们会完成的 通过对前列腺增生症患者和非疾病男性的前列腺组织进行前瞻性分析，以确定 如果炎症、增生、细胞因子和生长因子的表达与类固醇的合成有关 男性良性前列腺增生症的前列腺和下尿路症状。

Abstract Inflammation is very common in the adult prostate and it is associated with the development of benign prostatic hyperplasia (BPH). We do not know what the primary causes of inflammation in the prostate are, and we do not understand how it promotes prostate disease in men, but proposed mechanisms include released molecules from inflammatory cells that promote prostatic growth, and increases in steroid hormone levels made within the prostate in response to inflammation. The lack of a complete model system that mimics all aspects of human BPH is a key reason for this knowledge gap. Among the pathological features of advanced and highly symptomatic BPH are characteristic proliferative ringlet structures of intraepithelial hyperplasia termed “microglandular hyperplasia”. This terminology arises from the histological structures of small “micro” glands forming within epithelial nodules. Unlike other models of inflammation-induced hyperplasia of the rodent prostate, our recently published Toxoplasma gondii model of prostatic inflammation induces this histological patterning that is observed in humans, and is associated with symptoms similar to human BPH including increased urinary frequency and decreased urinary volumes. This suggests that mechanisms that induce both cell proliferation and tissue patterning might connect inflammation to hyperplasia and prostate disease, and our T. gondii model, which induces both components, would allow us to test this idea. Our hypothesis is that T. gondii-induced chronic prostatic inflammation promotes hyperplasia by promoting cytokine-mediated growth factor signaling and de novo biosynthesis of estrogen and testosterone. Prostatic hyperplasia in humans is associated with increased activity of IL-1 and IGF-1. Therefore in our first aim, we propose to determine if chronic inflammation induced by T. gondii infection induces proliferation in the prostate by activating the IL-1 to IGF-1 pathway. In this aim, we will employ a combination of molecular and pharmacological methods to assess the in vivo expression and production of inflammation-induced IL-1 and IGF-1 associated with hyperplasia and urinary symptoms in T. gondii-infected prostates. In the second aim, we will determine if T. gondii -induced microglandular hyperplasia results from induction of de novo steroid synthesis in the prostate, and we will assess the role of the druggable targets CYP17A1 and androgen and estrogen receptors in this process. We will also investigate the mechanism of how T. gondii induces steroid synthesis. Finally, we will determine if CYP17A1-driven steroid synthesis is associated with inflammation and microglandular hyperplasia in human BPH. It is known that de novo synthesis of androgen and estrogen occurs in prostates with BPH. We will finish with a prospective analysis of prostate tissue from men with BPH compared to non-diseased men to determine if inflammation, hyperplasia, and cytokine and growth factor expression, correlate with steroid synthesis in the prostate and lower urinary tract symptoms characteristic of BPH in men.